DESCRIPTION: (abstract verbatim) Uncontrolled complement activation plays a fundamental role in collateral host tissue damage during chronic inflammatory periodontal disease. Our preliminary evidence suggests that specific serum IgA1 antibodies (e.g., produced within the inflamed submucosal periodontal tissues), normally work in conjunction with serum C1-inhibitor (the rate-limiting component of the classical complement pathway) to be one of the main factors in properly regulating complement and limiting the subsequent immunopathological tissue damage. We hypothesize that to function properly, these IgA1 antibodies must escape digestion by bacterial IgA1 proteases. In preliminary studies, specific human IgA1 antibodies, when bound to immobilized dansylated-BSA (DNS-BSA) antigen, displayed a tightly controlled ability to activate the classical complement pathway. The tightly controlled C1 mediated C4b deposition was best detected after short incubation times with neat fresh human serum. We hypothesize that deposition of C4b on the alpha-1 tailpiece carbohydrate is important because of the subsequent weakened IgA1-C1 avidity resulting in enhancement of C1-inhibitor mediated irreversible elimination of C1 function. Genetically engineered human IgA1 mutant antibodies, deficient in carbohydrate in the CH2 region, exhibited C1 activating properties approaching human IgG1-DNS-BSA. Therefore, the tightly-controlled complement activation by specific IgA1 appears to be directly related to the position of the Fc-carbohydrate. We propose that IgA1 tightly regulates complement's role in submucosal immunity and inflammation and we are beginning to define a new role for IgA1 antibodies in controlling complement-mediated periodontal tissue damage. IgA1 function is especially necessary at the earliest stages of inflammatory periodontal disease, before local C1-inhibitor levels become partially depleted by neutrophil elastase. Genetically engineered human IgA1 antibodies (to dansyl), which have site-specific carbohydrate deficiencies on the CH2 and/or CH3/tailpiece will be used to accomplish the following objectives: 1) To ascertain a new function for IgA1 antibodies in regulating C1 via the enhancement of C1-inhibitor especially as a consequence of C4b and C3b deposition on the Fc-carbohydrate and to determine the overall affect on C1 and C1-inhibitor when IgA1 antibodies are co-deposited with IgG1 antibodies; and 2) To ascertain the relative potential of Fc alpha-1 fragments (released by specific bacterial IgA1 proteases) to bind C1q, activate C1 and/or to competitively block IgG1 immune complex and IgA1-immune complex interactions with C1. The results of these studies will provide needed information about the mechanisms that defeat proper complement-mediated host responses during inflammatory periodontal disease and will allow the systematic development of treatment strategies to prevent these harmful effects.